Familial Hypocalciuric Hypercalcemia Key wards: familial hypocalciuric hypercalcemia, parathyroid hormone, vitamin D, calcium The discovery and cloning of the calcium-sensing receptor

homeostatsis and the pathophysiology of disorders associated with abnormal CaSR activity including familial hypocalciruic hypercalcemia, neonatal severe hyperparathyroidism, and secondary hyperparathyroidism. The CaSR, a member of superfamily of G-protein-coupled receptors, has a large extracelluar domain and seven membrane-spanning segments (1). This receptor is localized on the surface of various tissues, including parathyroid cells, calcitonin-secreting C-cells of the thyroid, and various sites along the nephron. In the condition of hypocalcemia, increased parathyroid hormone (PTH) secretion mediated by CaSR stimulates the translocation of calcium into the extracellular fluid through a direct action of PTHon kidney and an indirect effect on intestine via 1 ,25-dihydroxyvitamin D3 [1 ,25-(OH)2D3] synthesis in the renal proximal tubular cells. Conversely, the activation of CaSR by hypercalcemia induces the suppression of PTHsecretion and calcium reabsorption via the renal tubular cells, thereby restoring the normal serum calcium concentration. Familial hypocalciruic hypercalcemia is an inherited disorder consistent with autosomal dominant transmission, resulting from inactivating mutations of CaSRof the heterozygous states (2). The reduced activity of CaSRon renal tubular cells and the parathyroid gland causes' enhanced renal tubular reabsorption of calcium and insufficient suppression of serum PTH concentration, both of which induce a rise in the serum calcium concentration. Biochemical findings for familial hypocalciruic hypercalcemia are characterized by mild to moderate hypercalcemia, mild hypermagnesemia, normal or mildly decreased serum phosphate concentration, and relatively low urinary calcium excretion (3). Serumconcentrations of PTH and 1,25-(OH)2D3 are paradoxically normal (3). The differentiation between familial hypocalciruic hypercalcemia and primary hyperparathyroidism is of great importance because of the distinct pattern of bone mineral density and the clinical strategy for management. The differential diagnosis of these two diseases was well reviewed by Lawand Heath (3). Although serum calcium concentrations in patients with familial hypocalciruic hypercalcemia are similar to those in patients with primary hyperparathyroidism, the urinary calcium excretion is lower in familial hypocalciuruic hypercalcemia than in primary hyperparathyroidism (4). The ratio of calcium clearance to creatinine clearance is generally less than 0.01 in familial hypocalciuruic hypercalcemia, whereas it is above 0.02 in primary hyperparathyroidism. In addition, a normal or slightly increased serum magnesiumconcentration is noted in familial hypocalciuruic hypercalcemia but not in primary hyperparathyroidism. A positive correlation exists between the serumconcentrations of calcium and magnesiumin familial hypocalciuruic hypercalcemia, but an inverse correlation exists between these two parameters in primary hyperparathyroidism (5). The urinary concentrating ability is not disturbed in familial hypocalciuruic hypercalcemia even in the presence of hypercalcemia, but its ability is disturbed in primary hyperparathyroidism (6). In the report of Hanibuchi et al, in this Journal (7), a 60year-old man with hypercalcemia was diagnosed as having familial hypocalciuric hypercalcemia.